Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent <i>In Vivo</i> Activities in Mouse Models of Hematological and Solid Tumors
Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound <b>26</b>, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of <b>26</b> as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with <b>26</b> and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.
Authors
- Stuart A. Fogarty
- KyuOk Jeon
- John Sensintaffar
- Stephen W. Fesik (ORCID: https://orcid.org/0000-0001-5957-6192)
- Plamen P. Christov (ORCID: https://orcid.org/0000-0002-2389-5535)
- Martin Aichinger
- Darryl B. McConnell (ORCID: https://orcid.org/0000-0002-2537-3458)
- Dorothea Rudolph (ORCID: https://orcid.org/0009-0003-5180-9635)
- Matthias Samwer (ORCID: https://orcid.org/0000-0003-4495-8619)
- Heribert Arnhof
- James M. Salovich
- Gordon M. Stott (ORCID: https://orcid.org/0000-0002-9148-6100)
- Florian Pierre Martin (ORCID: https://orcid.org/0000-0002-5968-5484)
- Nagarathanam Veerasamy
- Nagaraju Miriyala (ORCID: https://orcid.org/0000-0002-1265-738X)
- William Moore (ORCID: https://orcid.org/0000-0002-0929-2228)
- Norbert Schweifer (ORCID: https://orcid.org/0000-0002-0458-1792)
- Tobias Wunberg (ORCID: https://orcid.org/0000-0001-6521-8201)
- Harald Engelhardt (ORCID: https://orcid.org/0000-0001-8170-1893)
- Allison L. Arnold
- Bin Zhao (ORCID: https://orcid.org/0000-0003-0104-7508)
- Kwangho Kim (ORCID: https://orcid.org/0000-0001-9387-7642)
- Danielle Sgubin
- Taekyu Lee (ORCID: https://orcid.org/0000-0002-1957-427X)
- Edward T. Olejniczak
- Francesca Trapani
- James C. Tarr
Institutions
- Leidos (United States) (US)
- Vanderbilt University (US)
- Boehringer Ingelheim (Austria) (AT)
- Frederick National Laboratory for Cancer Research (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01188
- Citations
- 14
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- Basic Energy Sciences